Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance - PubMed (original) (raw)

Review

. 2021 Apr;26(4):e608-e621.

doi: 10.1002/onco.13627. Epub 2021 Jan 2.

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Review

Gamma Secretase Inhibitors in Cancer: A Current Perspective on Clinical Performance

Tyler R McCaw et al. Oncologist. 2021 Apr.

Abstract

Gamma secretase inhibitors (GSIs), initially developed as Alzheimer's therapies, have been repurposed as anticancer agents given their inhibition of Notch receptor cleavage. The success of GSIs in preclinical models has been ascribed to induction of cancer stem-like cell differentiation and apoptosis, while also impairing epithelial-to-mesenchymal transition and sensitizing cells to traditional chemoradiotherapies. The promise of these agents has yet to be realized in the clinic, however, as GSIs have failed to demonstrate clinical benefit in most solid tumors with the notable exceptions of CNS malignancies and desmoid tumors. Disappointing clinical performance to date reflects important questions that remain to be answered. For example, what is the net impact of these agents on antitumor immune responses, and will they require concurrent targeting of tumor-intrinsic compensatory pathways? Addressing these limitations in our current understanding of GSI mechanisms will undoubtedly facilitate their rational incorporation into combinatorial strategies and provide a valuable tool with which to combat Notch-dependent cancers. In the present review, we provide a current understanding of GSI mechanisms, discuss clinical performance to date, and suggest areas for future investigation that might maximize the utility of these agents. IMPLICATIONS FOR PRACTICE: The performance of gamma secretase inhibitors (GSIs) in clinical trials generally has not reflected their encouraging performance in preclinical studies. This review provides a current perspective on the clinical performance of GSIs across various solid tumor types alongside putative mechanisms of antitumor activity. Through exploration of outstanding gaps in knowledge as well as reasons for success in certain cancer types, the authors identify areas for future investigation that will likely enable incorporation of GSIs into rational combinatorial strategies for superior tumor control and patient outcomes.

Keywords: Cancer; Clinical trial; Gamma secretase; Gamma secretase inhibitors; Notch; Solid tumors.

© 2020 AlphaMed Press.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1

Figure 1

Schematic representation of Notch signaling pathway. A Notch receptor binds to cell‐bound or soluble Delta/Jagged ligands. Bound Notch is first cleaved by ADAM to release the extracellular portion. Gamma secretase then catalyzes a second cleavage event, liberating NICD into the intracellular space. NICD can interact with other pathways independent of transcriptional activity through noncanonical signaling or translocate to the nucleus, associate with CSL and MAML, and promote expression of target genes through canonical signaling.Abbreviations: GSI, gamma secretase inhibitor; MAML, mastermind‐like family; NICD, Notch intracellular domain.

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